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5. GENETIC BASIS OF SUBSTANCE DEPENDENCE

Other systems of interest
Cholecystokinin. The neuropeptide cholecystokinin (CCK) plays an important
role in the functioning of the central nervous system via an interaction with
dopamine and other neurotransmitters. The interaction of CCK with the
dopaminergic system has been implicated in the behaviours associated with
psychoactive drugs (Vaccarino, 1994; Crawley & Corwin, 1994).
Acute and chronic exposure to nicotine results in weight loss that is
associated with an increase in CCK in the hypothalamus; CCK antagonists
ameliorate symptoms of nicotine withdrawal, consistent with a role of the
CCK gene as a risk factor for smoking (Comings et al., 2001)

Opioid receptors. Both ethanol and opioids activate the mesolimbic dopamine
reward system, and genetic differences in the sensitivity of the endogenous
opioid system to alcohol may be an important factor in determining the risk
for the development of alcohol dependence or excessive alcohol consumption
(Gianoulakis, 2001). No consistent associations have been identified.

Glutamate transporter. Glutamate-mediated excitatory pathways play an
important role in the pathogenesis of alcohol dependence. The astroglial
glutamate transporter EAAT2 confers vulnerability to alcohol dependence;
however, no association of a polymorphism with alcohol dependence, or with
alcohol dependence with severe physiological withdrawal symptoms, or
alcohol dependence with antisocial behaviour, was observed (Sander et al.,
2000).

Confounding issues in linkage and candidate gene studies

Environment
Twin and family studies indicate a significant genetic risk for alcohol and
tobacco dependence and a substantial role for environmental factors
(Stoltenberg & Burmeister, 2000; Crabbe, 2002). It is important to remember
the latter source of variation in risk and to look for ways to integrate studies
of genetic and environmental influence (see later in this chapter). This
difficult task was reviewed for a series of complex disorders (Kiberstis &
Roberts, 2002). However, recent developments in genetics raise the possibility
of sorting out the complex interactions between genotype and environment
that determine the development of the individual behavioural phenotype.
This is clearly a direction that needs much attention.

Genetic heterogeneity
In addition to genetic and diagnostic heterogeneity, it is anticipated that
increased risk for many complex disorders such as substance dependence,
requires multiple genetic variants in combination (Stoltenberg & Burmeister,

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